The primary goal of this project is to investigate whether certain environmental exposures and genetic variants, either alone or in combination, affect the risk of developing Parkinson's disease (PD). We will investigate mechanisms that may explain the consistently observed inverse associations of cigarette smoking and caffeine consumption with PD, and the role of residential pesticide exposure on the risk of PD. In addition, existing and newly-identified polymorphisms in the coding and regulatory regions of candidate genes will be investigated, including genes that code for: (1) endogenous enzymes involved in metabolism of tobacco or caffeine, or in the detoxification of putative toxicants for PD, (2) proteins involved in dopamine regulation or metabolism, and (3) proteins that play a role in protein degradation and aggregation in dopaminergic neurons. We propose to expand a recently completed case-control study in a large health maintenance population of more than 500 newly diagnosed PD cases and 500 controls. Because preliminary data show that the strongest associations of genetic variants were observed among PD cases with early age at diagnosis (age less than or equal to 60), we will identify approximately 330 additional such cases along with age- and sex-matched controls. This new sample will be combined with that of the previous study, resulting in approximately 420 young diagnosis cases and 430 older diagnosis (age greater than 60) cases to be compared with 870 age- and gender-matched controls. Detailed information will be collected from all study subjects using in- person and telephone structured interviews including information on cigarette smoking, caffeine intake, and residential exposure to pesticides, along with other putative risk factors. Venous blood samples will be drawn for DNA extraction and genotyping assays for the gene polymorphisms of interest. By examining genetic polymorphisms within a group of carefully chosen candidate genes, in combination with extensive information about common environmental exposures, we hope to advance knowledge regarding both genetic and modifiable environmental risk factors for Parkinson's disease.